The present invention relates to the collection and accumulation of polarized noble gases, and relates more particularly to the determination of the level of polarization of hyperpolarized gases used in NMR and magnetic resonance imaging (xe2x80x9cMRIxe2x80x9d) applications.
It has recently been discovered that polarized inert noble gases can produce improved MRI images of certain areas and regions of the body which have heretofore produced less than satisfactory images in this modality. Polarized helium-3 (xe2x80x9c3Hexe2x80x9d) and xenon-129 (xe2x80x9c129Xexe2x80x9d) have been found to be particularly suited for this purpose. Unfortunately, as will be discussed further below, the polarized state of the gases are sensitive to handling and environmental conditions and can, undesirably, decay from the polarized state relatively quickly. Further, because of the sensitivity of the polarized gas, it is desirable to monitor the polarization level of the gas at various times during the product""s life. For example, in-process monitoring can indicate the polarization achieved during the optical pumping process (described below) or the polarization lost at certain phases of the life cycle process (so as to determine the remaining useable life of the polarized gas or to help identify critical production path issues).
Hyperpolarizers are used to produce and accumulate polarized noble gases. Hyperpolarizes artificially enhance the polarization of certain noble gas nuclei (such as 129Xe or 3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization. Such an increase is desirable because it enhances and increases the MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U.S. Pat. No. 5,545,396 to Albert et al., the disclosure of which is hereby incorporated herein by reference as if recited in fill herein.
In order to produce the hyperpolarized gas, the noble gas is typically blended with optically pumped alkali metal vapors such as rubidium (xe2x80x9cRbxe2x80x9d). These optically pumped metal vapors collide with the nuclei of the noble gas and hyperpolarize the noble gas through a phenomenon known as xe2x80x9cspin-exchange.xe2x80x9d The xe2x80x9coptical pumpingxe2x80x9d of the alkali metal vapor is produced by irradiating the alkali-metal vapor with circularly polarized light at the wavelength of the first principal resonance for the alkali metal (e.g., 795 nm for Rb). Generally stated, the ground state atoms become excited, then subsequently decay back to the ground state. Under a modest magnetic field (10 Gauss), the cycling of atoms between the ground and excited states can yield nearly 100% polarization of the atoms in a few microseconds. This polarization is generally carried by the lone valence electron characteristics of the alkali metal. In the presence of non-zero nuclear spin noble gases, the alkali-metal vapor atoms can collide with the noble gas atoms in a manner in which the polarization of the valence electrons is transferred to the noble-gas nuclei through a mutual spin flip xe2x80x9cspin-exchange.xe2x80x9d
In any event, after the spin-exchange has been completed, the hyperpolarized gas is separated from the alkali metal prior to introduction into a patient (to form a non-toxic pharmaceutically acceptable product). Unfortunately, both during and after collection, the hyperpolarized gas can deteriorate or decay relatively quickly (lose its hyperpolarized state) and therefore must be handled, collected, transported, and stored carefully. Thus, handling of the hyperpolarized gases is critical, because of the sensitivity of the hyperpolarized state to environmental and handling factors and the potential for undesirable decay of the gas from its hyperpolarized state.
Some accumulation systems employ cryogenic accumulators to separate the buffer gas from the polarized gas and to freeze the collected polarized gas. Co-pending and co-assigned U.S. patent application Ser. No. 08,989,604 to Driehuys et al. describes a suitable accumulator and method of cryogenically collecting, freezing, and then thawing frozen polarized xenon. The contents of this application are hereby incorporated by reference as if recited in full herein.
Conventionally, the level of polarization has been monitored at the polarization transfer process point (i.e., at the polarizer or optical cell) in a hyperpolarizer device or measured at a site remote from the hyperpolarizer after the polarized gas is dispensed from the hyperpolarizer. For example, for the latter, the polarized gas is directed to an exit or dispensing port on the hyperpolarizer and into two separate sealable containers, a gas delivery container, such as a bag, and a small (about 5 cubic centimeter) sealable glass bulb specimen container. This glass bulb specimen container is then sealed at the hyperpolarizer site and then carried away from the hyperpolarizer to a remotely located high-field NMR spectroscopy unit (4.7T) to determine the level of polarization achieved during the polarization process. See J. P. Mugler, B. Driehuys, J. R. Brookeman et al., MR Imaging and Spectroscopy Using Hyperpolarized 129Xe Gas; Preliminary Human Results, Mag. Reson. Med. 37, 809-815 (1997).
Generally stated, as noted above, conventional hyperpolarizers may also monitor the polarization level achieved at the polarization transfer process point, i.e., at the optical cell or optical pumping chamber. In order to do so, typically a small xe2x80x9csurfacexe2x80x9d NMR coil is positioned adjacent the optical pumping chamber to excite and detect the gas therein and thus monitor the level of polarization of the gas during the polarization-transfer process. The small surface NMR coil will sample a smaller volume of the proximate polarized gas and thus have a longer transverse relaxation time (T2*) compared to larger NMR coil configurations. A relatively large tip angle pulse can be used to sample the local-spin polarization. The large angle pulse will generally destroy the local polarization, but because the sampled volume is small compared to the total size of the container, it will not substantially affect the overall polarization of the gas.
Typically, the surface NMR coil is operably associated with low-field NMR detection equipment which is used to operate the NMR coil and to analyze the detected signals. Examples of low-field NMR detection equipment used to monitor polarization at the optical cell and to record and analyze the NMR signals associated therewith include low-field spectrometers using frequency synthesizers, lock-in amplifiers, audio power amplifiers, and the like, as well as computers.
In any event, it is now known that on-board hyperpolarizer monitoring equipment no longer requires high-field NMR equipment, but instead can use low-field detection techniques to perform polarization monitoring for the optical cell at much lower field strengths (e.g., 1-100 G) than conventional high-field NMR techniques. This lower field strength allows correspondingly lower detection equipment operating frequencies, such as 1-400 kHz.
For applications where the entire hyperpolarized gas sample can be located inside the NMR coil, an adiabatic fast passage (xe2x80x9cAFPxe2x80x9d) technique has been used to monitor the polarization of the gas in this type of situation. Unfortunately, in most production-oriented situations, this technique is not desirable. For example, in order to measure the polarization in a one-liter patient dose bag, a relatively large NMR coil and spatially large magnetic field is needed.
More recently, Saam et al. has proposed a low-frequency NMR circuit expressly for the on-board detection of polarization levels for hyperpolarized 3He at the optical cell inside the temperature-regulated oven which encloses the cell. See Saam et al., Low Frequency NMR Polarimeter for Hyperpolarized Gases, Jnl. of Magnetic Resonance 134, 67-71 (1998). Magnetic Imaging Technologies, Inc. (xe2x80x9cMITIxe2x80x9d) and others have used low-field NMR apparatus for on-board polarization measurement.
However, there remains a need to be able to efficiently and reliably determine and/or monitor the level of polarization of polarized gases in various points in the production cycle. This is particularly important for the flowing production modality used for cryogenically accumulated 129Xe, which as noted above, is frozen and thawed during the production cycle.
In view of the foregoing, it is an object of the present invention to provide methods and apparatus to efficiently monitor the hyperpolarization level of a quantity of hyperpolarized gas at various points in the production cycle.
It is an additional object of the present invention to provide a hyperpolarizer with means to monitor the polarization level of cryogenically accumulated hyperpolarized gas both before the gas is frozen and after the gas is thawed.
It is another object of the present invention to provide a method and device for monitoring the polarization level of flowing hyperpolarized gas which can be used in a substantially continuous gas-flow production environment.
It is a further object of the present invention to provide an apparatus and method which reduces the complexity and number of components needed to monitor the level of polarization in the polarized gas both during the optical pumping process and subsequent to the optical pumping process.
It is still another object of the present invention to provide an apparatus to monitor the polarization level of frozen polarized gas.
It is an additional object of the present invention to provide an apparatus that can improve the predictability of a cryogenic hyperpolarized gas production process.
It is a still further object of the present invention to provide an apparatus that can reliably yield sufficient levels of polarized gas during post accumulation thaw.
These and other objects are satisfied by the present invention by a hyperpolarizer apparatus with one or more NMR coils configured to provide xe2x80x9con-boardxe2x80x9d polarization monitoring level information at more than one point during the production cycle. In a preferred embodiment, the hyperpolarizer includes a dual symmetry NMR coil configuration which allows the same NMR coil and detection circuit to be used to measure 129Xe polarization both in the optical cell before cryogenic accumulation and in a post thaw bulb after cryogenic accumulation thawing.
In particular, a first aspect of the invention is directed to a hyperpolarizer for producing polarized noble gases. The hyperpolarizer comprises an optical pumping cell having a non-polarized gas inlet port and a polarized gas outlet port and a magnetic field source operably associated with the optical pumping cell. The magnetic field source is configured to provide a region of homogeneity. The hyperpolarizer also includes a NMR coil having first and second opposing ends. The first end is positioned adjacent the optical pumping cell within the region of homogeneity. The hyperpolarizer also includes a cryogenic accumulator in fluid communication with the optical pumping cell outlet port and a polarized gas dispensing port in fluid communication with the cryogenic accumulator. A polarized gas exit flow path extends between said cryogenic accumulator and the polarized gas dispensing outlet and a secondary reservoir is positioned adjacent the NMR coil second end in fluid communication with the polarized gas exit flow path. During operation of the hyperpolarizer, the NMR coil is configured to excite one of a quantity of polarized gas positioned in the optical cell and a quantity of polarized gas positioned in the secondary reservoir. Preferably, the NMR coil primarily monitors the polarization in the optical cell during operation of the cell, but during post-thaw, the polarization in the optical cell is gone and the only measurable signal will arise from the polarized gas in the post thaw bulb.
In a preferred embodiment, the magnetic field source defines a region of homogeneity which includes a portion of the optical pumping cell and a (spatial) volume which extends a distance below the optical pumping cell. The NMR coil is positioned on a bottom portion of the optical pumping cell, and the NMR coil and at least a portion of the secondary reservoir are positioned within the region of homogeneity.
Another aspect of the present invention is a secondary reservoir for a hyperpolarizer unit. The secondary reservoir is configured to hold a quantity of hyperpolarized noble gas therein and comprises opposing first and second end portions defining a gas flow path therebetween. The first end portion is configured to capture a quantity of hyperpolarized gas therein. The second end-portion has an opening formed therein and is configured to engage with a portion of a (hyperpolarized) gas flow line. Preferably, the first end is configured with a thin wall.
An additional aspect of the present invention is a dual symmetry NMR coil for monitoring the level of polarization associated with polarized gas in two different locations. The dual symmetry NMR coil comprises first and second opposing flanges and an intermediate coil section positioned therebetween. The thickness of the first and second flanges are substantially the same.
Still another aspect of the present invention is a hyperpolarizer for producing polarized noble gases. The hyperpolarizer comprises an optical pumping cell having a primary body and a longitudinally extending polarized gas outlet port with an outer surface. The hyperpolarizer includes a magnetic field source operably associated with the optical pumping cell. The magnetic field source is configured to provide a region of homogeneity. The hyperpolarizer also includes a first NMR coil having first and second opposing ends and defining a center aperture therethrough. The first NMR coil is positioned on the outlet port such that the outlet port longitudinally extending portion extends through the first NMR coil aperture. The first end of the first NMR coil being positioned adjacent the primary body of the optical pumping cell within the region of homogeneity. During operation of the hyperpolarizer, the first NMR coil is configured to excite a quantity of polarized gas positioned proximate to the optical cell outlet port. In a preferred embodiment, the hyperpolarizer includes a second and third NMR monitoring coil positioned at other selected points in the production cycle.
A preferred method of operating an NMR coil positioned proximate to the optical cell outlet port, includes flowing the hyperpolarized gas through the optical cell and out the port at a desired rate. The hyperpolarized gas flow is preferably temporally stopped or slowed and a NMR signal is taken via the coil on the outlet port (or arm) and the flow is then resumed. This configuration and method can generate a signal which is representative of the flowing hyperpolarized gas as it exits the optical cell.
Another aspect of the present invention is directed to another hyperpolarizer embodiment for producing optically pumped polarized noble gases. The hyperpolarizer comprises an optical pumping cell having a non-polarized gas inlet port and a polarized gas outlet port and a primary body. The hyperpolarizer also includes a cryogenic accumulator in fluid communication with the optical pumping cell outlet port. The cryogenic accumulator comprises an elongated closed end tube defining a polarized gas collection chamber for holding a quantity of collected polarized gas therein. The gas collection chamber is operably associated with first and second sealable valves. The cryogenic accumulator also includes a cryogenic bath, wherein the collection chamber is immersed into the cryogenic bath. The cryogenic accumulator also includes a set of permanent magnets arranged to provide a magnetic field with a region of homogeneity adjacent the collection chamber in the cryogenic bath and a first NMR coil positioned in the cryogenic bath adjacent the closed end of the tube in the magnetic field region of homogeneity. The hyperpolarizer also includes a polarized gas dispensing outlet in fluid communication with the cryogenic accumulator and a polarized gas exit flow path extending from the cryogenic accumulator to a polarized gas dispensing outlet. During operation of the hyperpolarizer, the first NMR coil is configured to monitor the level of polarization in the polarized gas in the closed end of the collection tube.
Yet another aspect of the present invention is a method for monitoring the polarization level of polarized gas during production. The method includes polarizing a quantity of noble gas in an optical pumping chamber and directing the polarized noble gas in the optical pumping chamber to a gas collection path. A magnetic field having a region of homogeneity is provided; the region of homogeneity preferably includes at least a volume of space associated with a portion of the optical pumping chamber and the gas collection path proximate to the optical pumping chamber. A first NMR coil is positioned adjacent the gas flow path in the magnetic field region of homogeneity and the polarized gas is excited by transmitting an excitation signal to the first NMR coil. The level of polarization associated with the hyperpolarized gas adjacent to the NMR coil is measured to thereby monitor the level of polarization associated with the polarized gas in a region of the polarizer adjacent the polarized gas flow path.
In a preferred embodiment, the optical pumping chamber has a primary body portion and a polarized gas exit port defined by a longitudinally extending leg, and the NMR excitation coil is positioned around the leg adjacent the primary body portion of the optical pumping chamber. It is also preferred that the method further comprise cryogenically accumulating the polarized gas in a cryogenic accumulator during which a portion of the polarized gas is frozen and then subsequently thawing the frozen polarized gas prior to the dispensing step and after the thawing step. It is also preferred that during or after the thawing step, a minor portion of the quantity of thawed polarized gas is directed away from a major portion of the hyperpolarized gas into the gas flow path proximate to the NMR coil.
Yet still another aspect of the present invention is directed to a hyperpolarized gas optical pumping cell having an integrated NMR coil. The integrated cell includes an optical pumping cell which has a primary body and at least one longitudinally extending leg portion. The integrated cell also includes a NMR coil having opposing first and second ends and an aperture formed through the center thereof. The first end is configured to receive a portion of said longitudinally extending leg therein and attach to the optical pumping cell. Preferably, the NMR coil attaches to the leg adjacent the primary body along the gas exit flow path.
It is an additional aspect of the present invention to provide a method for releasing the post-thaw cryogenically accumulated hyperpolarized gas in a hyperpolarizer having a cold finger collection container and exit flow path plumbing associated therewith. The method includes the steps of cryogenically accumulating a quantity of frozen hyperpolarized gas in a cold finger and monitoring a pressure associated with the cryogenically collected gas in the cold finger. (After cryogenic accumulation, flow is stopped and residual gases are evacuated, and heat is applied to start the thaw). At least a portion of the quantity of frozen hyperpolarized gas in the cold finger is thawed. The pressure in the cold finger is increased in response to the phase transition of the frozen hyperpolarized gas from a substantially frozen sample into a thawed fluid sample. The thawed hyperpolarized fluid sample is released as a gas from the cold finger responsive to a predetermined pressure associated with the cold finger corresponding to said monitoring step. In a preferred embodiment, the frozen gas transitions directly to a liquid phase and releasing step is performed in response to the opening of a valve downstream of the cold finger in the hyperpolarizer and both the thawing and releasing steps are performed on-board the hyperpolarizer.
Advantageously, the present invention can monitor the polarization during production and even at the dispensing port where convenient MRI patient-sized quantities (such as 0.5-2 liters of polarized gas) are directed out of the hyperpolarizer. As such, the polarization level at shipping or before storage is readily identifiable before the container is detachably released from the hyperpolarizer unit for easy transport to a remote site. The improved on-board in-process polarization monitoring can improve production and conveniently indicate the level of polarization of gas at several key points including at the dispensing port. Further, the dual symmetry NMR coil can allow a single NMR coil to measure polarization both at the optical cell during the optical pumping process and at a second point in the production cycle, such as at a post-thaw position. Further, the instant invention now configures a cold finger to release cryogenically accumulated hyperpolarized xenon dependent on a more predictable indicator, pressure. Because the release of the thawed gas at a predetermined pressure is less dependent on process variations such as flow rates and collected quantities of gas, a more predictable process can be obtained, thereby providing a more reliably controllable production capability.
The foregoing and other objects and aspects of the present invention are explained in detail herein.